title: Anti-apoptotic Bcl-2 family member Mcl-1 regulates cell viability and bone-resorbing activity of osteoclasts.
abstract: Myeloid cell leukemia sequence 1 (Mcl-1) is an anti-apoptotic Bcl-2 family protein and an immediate early gene expressed during myeloid leukemia cell line differentiation. We analyzed the expression and function of Mcl-1 in osteoclasts. Mcl-1 protein exhibited a short half-life in osteoclasts caused by its degradation in the ubiquitin-proteasome system. Mcl-1 had no effect on osteoclast differentiation, but its overexpression prolonged osteoclast survival and suppressed the bone-resorbing activity of these cells, as determined by pit formation assay. Conversely, Mcl-1 depletion suppressed osteoclast survival and increased bone resorption. This negative role for Mcl-1 on the bone-resorptive activities of osteoclasts may be caused by the increase in adenosine triphosphate/adenosine diphosphate ratio. Finally, we showed that the local deletion of Mcl-1 by the injection of the Cre adenovirus into the calvaria of Mcl1(fl/fl) mice significantly affected GST-RANKL-induced bone resorption in vivo. These results demonstrated that Mcl-1 positively regulates cell viability and negatively regulates the bone-resorbing activity of osteoclasts both in vitro and in vivo.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hironari
authors.initials: H
authors.lastname: Masuda
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Omata
authors.forename: Naoto
authors.initials: N
authors.lastname: Tokuyama
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yasui
authors.forename: Yuho
authors.initials: Y
authors.lastname: Kadono
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex
keywords: Apoptosis; Bone resorption; Cell signaling; Osteoclast; Remodeling